Modified phenolic stilbenes as antifertility agents

ABSTRACT

DESCRIBED ARE CERTAIN 1,1-BIS(TRIFLUOROMETHYL)-2,2-DIPHENYLETHYLENES, WHICH CARRY AN OXY GROUP IN THE PARA POSITION OF AT LEAST ONE BENZENE RING. THESE NEW COMPOUNDS, AS WELL AS THEIR PARENT COMPOUND, 1,1-BIS(TRIFLUOROMETHYL)-2,2-DIPHENYLETHYLENE, ARE EFFECTIVE IN PREVENTING PREGNANCY IN WARM-BLOODED ANIMALS AND CAN BE ADMINISTERED AFTER COITUS.

United States Patent 3,751,485 MODIFIED PENOLIC STILBENES ASANTIFERTILITY AGENTS William J. Middleton, Chadds Ford, Pa., assignor toE. I.

du Pont de N emours and Company, Wilmington, Del. No Drawing. Originalapplication Oct. 31, 1969, Ser. No.

873,124. Divided and this application Nov. 15, 1971,

Ser. No. 198,952

Int. Cl. C072 43/28 US. Cl. 260-612 R 4 Claims ABSTRACT OF THEDISCLOSURE Described are certain1,l-bis(trifiuoromethyl)-2,2-diphenylethylenes, which carry an oxy groupin the para position of at least one benzene ring. These new compounds,as well as their parent compound,l,l-bis(trifiuoromethyl)-2,2-diphenylethylene, are effective inpreventing pregnancy in warm-blooded animals and can be administeredafter coitus.

RELATED APPLICATION This application is a division of my copendingapplication Ser. No. 873,124 filed Oct. 31, 1969 and now Pat. No.3,678,117.

BACKGROUND OF THE INVENTION This invention relates to novel 1,1-bis(trifiuoromethyl) 2,2-diphenylethylenes, wherein the para position of atleast one benzene ring has an oxy group. This invention further relatesto the use of these compounds in the prevention of pregnancy.

At present, there are Widely used antifertility agents which act toestablish a pseudopregnant condition in the female and thereby preventovulation. In general, they are mixtures of estrogens and progestins,and they must be taken daily during a major portion of the menstrualcycle. Unfortunately, administration of these mixtures can result inside effects similar to those commonly occurring during early pregnancy.

There is a need, however, for antifertility agents which can beadministered after coitus and which do not have the undesirablepseudopregnancy side effects.

SUMMARY OF THE INVENTION Now, according to this invention, it has beendiscovered that certain new1,l-bis(trifluoromethyl)-2,2-diphenylethylenes are efiectiveantifertility agents for warmblooded female animals when administeredafter coitus. It is probable that the mechanism of action is such thatniclation is prevented. Compounds of this invention are easy to use anddo not cause pseudopregnancy side effects.

The novel compounds are 1,l-bis(trifluoromethyl)-2,2- diphenylethylenes(alternatively named3,3,3-trifluoro-l,ldiphenyl-Zdrifluoromethylpropenes) having the formula3,751,485 Patented Aug. 7, 1973 DETAILED DESCRIPTION OF THE INVENTIONRepresentative R groups which are contemplated by this invention are:methyl, ethyl, butyl, hexyl, octyl and dodecyl, including both straightchain and branched radicals; hydroxyethyl, hydroxypropyl, hydroxyhexyl,hydroxynonyl, dimethylaminomethyl, dimethylaminoethyl,diethylaminoethyl, dipropylaminobutyl, dibutylaminohexyl,N-morpholinoethyl, N-piperidinopropyl, N-pyrrolidinomethyl, formyl,acetyl, propionyl, cyclohexanonyl, decanoyl, lactoyl, salicyl,'diethylaminoacetyl dimethylaminobutyryl, benzoyl, l-naphthoyl and4-toluyl. The preferred compounds of this invention are those in whichat least one of the R groups is hydrogen, a C C alkyl group, or a C -Cacyl group.

The diphenylethylenes in which X is hydrogen and R is alkyl can beprepared by the reaction of1,1-bis(trifluoromethyl)2-fluoro-2-phenylethylene with ap-alkoxyphenyllithium, as illustrated by the following equation.

The diphenylethylene in which R is H can be prepared similarly by thereaction of 1,1-bis(trifluoromethyl)-2- fluor0-2phenylethylene with thelithium salt of p-hydroxyphenyllithium, followed by acidification, asillustrated by the following equation.

Q fi

C=C MO m.

The diphenylethylenes in which both phenyl rings contain identical ORgroups, with R being either hydrogen or alkyl, can be prepared by thereaction of one equivalent of perfluoroisobutylene with two equivalentsof p-alkoxyphenyllithium as illustrated by the following equation:

znoQ-m 2= (CFa)z RQQ or;

or with two equivalents of the lithium salt of p-hydroxyphenyllithium.

The diphenylethylenes in which the two phenyl rings containnon-identical OR groups can be prepared by the reaction of a 1,1,bis(trifiuoromethyl) 2-fluoro-2-palkoxyphenylethylene with aphenyllithium containing a different p-alkoxy group.

The 1,1-bis (trifiuoromethyl -2-fluoro-2-pheny1ethy1enes used in theseprocedures can be prepared by the reaction of phenylmagnesium halide orp-alkoxyphenylmagnesium halide with perfluoroisobutylene, which is awell known compound described, i.e., in U.S. 2,617,836.

All of these reactions between the fluoroolefins and lithium compoundsare conducted in the presence of an inert solvent such as diethyl etheror an aliphatic or aromatic hydrocarbon. The optimum reactiontemperature is between -80 and +40 C., and the optimum pressure isbetween V2 and 3 atmospheres, the atmospheric pressure being the mostconvenient to employ. The prodnets of the reaction can be isolated andpurified by conventional techniques such as distillation,recrystallization, and chromatography.

The diphenylethylenes of this invention in which R is alkyl can also bemade by first contacting hexafluorothioacetone with a p-alkoxy or ap,p'-dialkoxydiphenyldiazomethane in an inert hydrocarbon,chlorohydrocarbon, or ether solvent at a temperature between 80 and +40C. to form an episulfide which next is thermally desulfurized attemperatures of about 100250= C., as illustrated by the followingequation.

EXAMPLE 1 1,l-bis(trifiuoromethyl)-2-phenyl-2-(4-'hydroxyphenyl)ethylene A solution of 13.84 g. (0.08 mole) ofp-bromophenol in 100 ml. of ether was added dropwise to 0.16 mole ofbutyllithium in 200 ml. of 50/50 ether-hexane. The reaction mixture wasstirred for 1 hour at room temperature, and then a solution of 20.8 g.(0.08 mole) of lfluoro-2,2-bis(trifluoromethyl)-1-phenylethylene in 25ml. of ether was added dropwise over 15 min. The reaction mixture wasstirred for 1 hour, then mixed with 200 ml. of HCl. The ether layer waswashed with water,

dried g and distilled to give 7.1 g. of a colorless liquid, B.P. 121-125(0.2 mm.) that solidified on cooling. Recrystallization from pentanegave 6.5 g. of 1,1- bis(trifluoromethyl)-2-phenyl-2-(4hydroxyphenyl)-ethylene as colorless needles: M.P. -l06 C.; P NMR(acetone) 6 54.7 (m, A B IR (KBr) 2.99 1 (OH); UV (ethanol) x 306 m (69,900), 275 (e 10,200) and 232 (5 13,700).

Analysis.Calcd. for C H F O (percent): C, 57.84; H, 3.03; F, 34.32.Found (percent): C, 57.97; H, 3.15; F, 34.21.

The l-fluoro-2,2-bis(trifluoromethyl)-1-phenylethylene used in thisexample was prepared in the following manner:

Perfiuoroisobutylene (68 ml. measured at 78 C., 0.6 mole) was slowlydistilled over a period of 1.5 hours into a solution of 0. 66 mole ofcommercial phenylmagnesium bromide in ether (440 ml.) cooled to 510 C.Aqueous 10% hydrochloric acid, 250 ml., was added, the organic layerseparated, washed with water, and dried (MgSO Distillation gave 103 g.(67%) of 1-fluoro-2,2-bis(trifluoromethyl)-l-phenylethane as a colorlessliquid: B.P. 84-85 C. (50 mm.); n 1.4179; IR (liquid) 5.98 1 (C=C); UV(EtOH) 1,-bis (trifluoromethyl)-2-phenyl-2- (4-acetoxyphenyl)ethyleneX=H, R=acetyl H (OHaCO) O (I) CHAOQ A solution of 2.5 g. of1,1-bis(trifluoromethyl)-2-phenyl-2-(4-hydroxyphenyl)ethylene in 10 m1.of acetic anhydride was heated at reflmr for 2 hours. Water, 50 ml., wasadded to decompose the excess anhydride, and the solid that separatedwas collected on a filter, washed with water, and recrystallized frompentane. There was obtained 2.3 g. of1,l-bis(trifiuoromethyl)2-phenyl-2-(4- acetoxyphenyDethylene ascolorless crystals; M.P. 84- 86 C.; F NMR (CCl F) 6 55.7 p.p.m. (s); HNMR (CCl F) 'r 2.6-3.0 (m, 9H) and 'r 7.89 (m, CH IR (KBr) 5.62 (0:0);UV (ethanol) A 262 ma (5 10,600) and 221 (e 14,600).

Analysis.-Calcd. for C H F O (percent): C, 57.76; H, 3.23; F, 30.46.Found (percent): C, 57.50; H, 3.49; F, 30.52.

EXAMPLE 3 1,l-bis(trifluoromethyl)-2,2-di- (4-ethoxyphenyl) ethyleneX=OR, R=ethyl An 80.4 g. sample (0.4 mole) of p-bromophenetole was addeddropwise to a solution of 0.4 mole butyllithium in 500 ml. of 50/50ether-hexane. The reaction mixture was stirred at room temperature for 1hour, and then cooled in an ice bath. Perfiuoroisobutylene, 25 ml.measured at -78 C. was slowly distilled into the reaction mixture over aperiod of 30 minutes. Aqueous hydrochloric acid, 200 ml., was added andthe organic layer was separated, washed with Water, dried (MgSO anddistilled to give 40 g. of a colorless liquid, B.P. 148158 C. (0.2 mm.)that solidified upon cooling. Recrystallization from pentane gave 30.1g. of 1,1-bis (trifluoromethyl)-2,2-di(4- ethoxyphenyDethylene ascolorless crystals: MP. 71- 73 C.; P NMR (CCl F) 5 55.3 p.p.rn. (s); HNMR CC1 F) 1- 3.13 (m, A 13 8H), 7 6.05 (quartet, 1 =7 Hz., 4H) and 'r8.65 (t, J=7 Hz., 6H); UV (ethanol) a 300 m (6 18,600) and 229 my. (618,300).

AnaZysis.Caled. for C I-1 F 0 (percent): C, 59.41; H, 4.49; F, 28.19.Found (percent): C, 59.48; H, 4.62;

EXAMPLE 4 l,1-bis(trifluoromethyl) -2,2-di(4-methoxyphenyl) ethyleneX=OR, R=methyl 4-bromoanisole, 20.6 g. (0.11 mole) was added drop- Wiseover 20 min. to 0.1 mole of butyllithium in 60 ml. of hexane solution,and the reaction mixture was stirred for 30 min. A 50 ml. portion ofether was added to bring the precipitated solids into solution, and then23 g. (0.08 mole) of 1 fluoro 2,2-bis(trifiuoromethyl)-1-(4-methoxyphenyDethylene was added dropwise over 30 min. Cooling wasmaintained to keep the temperature between 25-40 C. Aqueous 10%hydrochloric acid, 100 ml., was added and the organic layer wasseparated, Washed with water, and dried (MgSO Distillation gave 16.5 g.(55%) of 1,1 bis(trifiuoromethyl) 2,2-di(4- methoxyphenyl)ethylene as aviscous liquid, B.P. 130- 134 C. (0.06 mm.), that crystallized inpentane to give colorless needles:

M.P. 77-78; F NMR (CCl F) 6 55.3 p.p.m. (s); H NMR (CCl F) 1- 6.28 (s,6H) and 1- 3.07 (m, 8H); and UV (EtOI-l) A 229 m (6 18,300), 229 me (617,000).

Analysis.Calcd. for C H F O (percent): C, 57.45; H, 3.75; F, 30.30.Found (percent): C, 57.66; H, 3.66; F, 30.25.

Deep purple solutions are formed when this material is dissolved instrong acids such as trifluoroacetic acid or 60% sulfuric acid. Thespectral evidence of a solution in 98% sulfuric acid indicates that astable carbonium ion is formed:

P NMR (98% H 50 6 59.7 p.p.m. (d, J=7.7 Hz.); UV (98% H 50 545 m (e40,200), 345 my. (e 9,580) and m (6 8,000).

muglgm.

The 1 fluoro-2,2-bis(trifiuoromethyl)-l-(4-methoxyphenyl) ethylene usedin this example was prepared in the following manner:

A 56.12 g. sample (0.3 mole) of pbromoanisole was added dropwise to 8.00g. (0.33 mole) of magnesium turnings in 500 m1. of ether. Grignardformation was complete in about 2 hours. The solution was cooled to15-20 C. 34 ml. (ca. 0.3 mole) of perfiuoroisobutylene was distilledinto the solution over a period of 30 min., and then 200 ml. of aqueous10% hydrochloric acid was added. The ether layer was separated, washedwith water, dried (MgSO and then distilled. There was obtained 56.5 g.(65%) of 1 fluoro-2,2-bis(trifluoromethyl)-l- (4-methoxyphenyl) ethyleneas a colorless liquid: B.P. 81- 82 C. (5.2 mm), r1 1.4534; 1r (liquid)6.18; (C=CF); UV (EtOH) A 282 my. (6 14,900), 218 me (6 9,730); F NMR(neat) 6 56.4 (quartet J=8.5 Hz. to (1, 1:10 Hz., 3F), 58.7 (quartetJ=8.5 Hz. to d, J=24 Hz, 3F), 64.9 (m, 1F).

Analysis.-Calcd. for C H F O (percent): C, 45.85; H, 2.45; F, 46.15.Found (percent): C, 46.15; H, 2.50; F, 46.42.

EXAMPLE 5 1, l-bis (tn'fiuoromethyl -2 (4-methoxyphenyl) -2-phenylethylene X=H, R=methyl N-NH;

c...o@ l@ ..o

Hexafiuorothioacetone was added portionwise to this solution ofphenyl-4-methoxyphenyldiazomethane in methylene chloride cooled to 30 C.until the purple solution faded to yellow. The solvent was removed byevaporation, and the residue was redissolved in pentane. The pentanesolution was filtered to remove the sulfur, and the filtrate wasdistilled. There was obtained 7.2 g. of 1,1 bis(trifiuoromethyl) 2(4-methoxyphenyl)-2- ethylene as a nearly colorless liquid, B.P. 102-103C. (0.2 mm.), 22 15266. The F NMR (CClF showed a multiplet (87%integrated area) at 55.4 ppm. from CClF and absorptions (13% total) dueto impurities at 61.1, 64.6, and 64.8 ppm.

Analysis.-Calcd. for C H F O (percent): C, 58.96; H, 3.50; F, 32.92.Found (percent): C, 60.04; H, 3.87; F. 30.08.

7 EXAMPLE 6 1, l-bis (trifluoromethyl) -2-phenyl-2- [4- fl diethyl aminoethoxyphenyl]-ethylene citrate X=H, R=diethylaminoethyl A 0.85 g. sample(0.007 mole) of B-chlorotriethylamine was added to a solution of 1.66 g.(0.005 mole) of 1,1-bis (trifluoromethyl)-1-phenyl-l (4 hydroxyphenyl)ethylene in aqueous 5% sodium hydroxide. The oil that precipitated wascollected in 75 ml. of ether, and the ether extract was dried oversodium hydroxide pellets and then mixed with a solution of 1.1 g. (0.005mole) of citric acid in 200 ml. of wet ether. The precipitate thatformed Was collected on a filter, washed with ether, and dried in air togive 1.6 g. of a white powder. Recrystallization from acetone gave 1.1g. of 1,1-bis(trifluoromethyl)-2-phenyl-2- [4-(fldiethylarnino)cthoxyphenyl] ethylene citrate as colorless crystals; M.P.134136 C.; F NMR (acetone-d6) 6 54.1 p.p.rn. (multiplet, CF

Analysis.-Calcd. for C H F NO (percent): C, 53.93; H, 5.01; N, 2.25.Found (percent): C, 52.28; H, 5.03; N, 2.46.

Additional examples of preferred routes to other diphenylethylencs ofthis invention are listed in the following Table I.

TAB LE I Reactants Product F CF:

CHO- CF H 3 Q 31,1-bis(trifluoromethyl)-2-(phydroxyphenyl)-2-(p-methoxyphenyDethyleneHOQ C F:

+ (CH COhO a ll HsC-O-Q or,

1,1-bis(trifluoromethyl)-2-(p-methoxyphenyl)-2-(p-acetoxyphenyl)ethyleneGEN-Q CF;

C=C OICHzCHr-N HO-Q/ \CF:

cum-Q or,

1,1-bis(trifluoromethyD-Z-(p-methoxyphenyl)-2-(p-2-pyrro1idinoethoxyphenyl)ethylene1,1-bis(tritiuoromethyl)-2,2-bis(p-hydroxyphenyDethylene 01130 0Q CFa1,1-bis(trifluoromethyl)-2,2-bis(p-aeetoxyphenyl) ethylene1,1-bis(trifluoromethyl)-2-phenyl-2-(pbenzoy1oxypheuyl)ethylene O=C\lid-Q CF:

n EH1,l-bis(trifluoromethyD-2-phenyl-2-(p-l-adamantoyloxyphenyl)ethylenecum-Q 01a 1,1-bis(trifluor0methy1)-2-(p-methoxy heny1)-2-( -Z-iperidinoethoxy henyl)ethylene TABLE IContinued Reactants Product on or:onto-Q or. 1 Q (3:0 -I- ClCHzC-HzOH C=C\ HOQ OF: H0CH2CH2O/ or;

1,l-bis(trifluoromethyl)-2-(p-methoxyphenyl)-2-(p-2-hydroxyethoxyphenyl)ethylene Nomorno U1,1-bis(trifluoromethyl)-2(p-methoxyphenyl)-2-(p-2-morpholinoethoxyphenybethyleneo=c @0001 HOQ/ or;

1,l-bis(trifluoromethyl)-2-phenyl-2-(p2-cyelohexenylcarbonyloxyphenyl)ethylenei N aO- C F Q a @HMCW C=C (C2Hs)2NCH2COOH C1,1-his(trifluoromethyl)-2-phenyl'2-tp-diethylaminoaeetoxyphenyl)ethylene.

The new compounds of this invention, as well as their parent compound,1,1,1-bis(trifluoromethyl)-2,2-diphenylethylene, are useful inprevention of pregnancy in warmblooded animals. The compounds can beadministered by any suitable means. Oral administration is preferred.Administration also can be parenteral, that is subcutaneous orintramuscular, or rectal. The compounds are preferably administered in asingle dose, preferably orally, after coitus, but before implantation ofthe fertilized egg. Alternatively, single or divided doses can beadministered daily during all or a substantial fraction of the estrouscycle or menstrual cycle.

Doses will ordinarily range from about 00005 to about 50 milligrams perkilogram of body weight of the recipient per day (mg./kg.-day). Thepreferred dosage range is from about 0.0025 to about mg./kg.-day, andthe most preferred range is from about 0.005 to about 5 rug/kg.- day.

These compounds can be employed with satisfactory results to preventpregnancy in laboratory animals such as rats, mice, guinea pigs,rabbits, monkeys and chimpanzees and are also effective in preventingpregnancy in domestic animals such as swine, cows, sheep and horses. Insmall animals it is usually convenient to administer them in the form ofa capsule, or incorporate them in the animal feed. For large animals,parenteral administration is often preferred.

These compounds can be employed in useful compositions in such dosageforms as tablets, capsules, powder packets, or liquid solutions,suspensions, or elixirs for oral administration or liquid solutions forparenteral use, and in certain cases, suspensions for parenteral use. Insuch compositions, the active ingredient will ordinarily always bepresent in the amount of at least 0.01% by Weight based on the totalweight of the composition and not more than 90% by weight.

Besides the active 1,1 bis(trifiuoromethyl) 2,2 diphenylethylenes, thecomposition will contain a solid or li uid non-toxic pharmaceuticalcarrier for the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, thesolid carrier is a capsule which can be of the ordinary gelatin type.The capsule will contain from about 0.03-% by weight of the activecompound and 99.9725% of a carrier.

In another embodiment, the active ingredient is tableted with or withoutadju'vants. In yet another embodiment, the active ingredient is put intopowder packets. These capsules, tablets and powders will usually containabout 0.03% to and preferably 0.1% to 70% by weight of activeingredient. These dosage forms preferably contain about 0.1 to 700milligrams of active ingredient, a quantity of about 0.03 milligram to350 milligrams being most preferred.

The pharmaceutical carrier can be a sterile liquid such as water andoils, including those of petroleum, animal, vegetable or syntheticorigin, for example, peanut oil, soybean oil, mineral oil, sesame oil,and the like. In general, water, saline, aqueous dextrose (glucose) andrelated sugar solutions, and glycols such as propylene lycol orpolyethylene glyeols are preferred liquid carriers, particularly forinjectable solutions. Sterile injectable solutions, such as saline, willordinarily contain about 0.0035 to 25%, and preferably about 0.01% to 5%by weight of the active ingredient.

Suitable formulations for oral administration can be prepared in asuspension, syrup or elixir in which the active ingredient ordinarilywill constitute about 0.0007 to 5% and preferably about 0.003 to 1% byWeight. The pharmaceutical carrier in such composition can be an aqueousvehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in RemingtonsPharmaceutical Sciences by E. W. Martin, a well-known reference text inthis field.

The following examples further illustrtae the fertility control inwarm-blooded animals by the process of the present invention.

I EXAMPLE A Immature female rats (28 days old) are induced intoprecocious puberty with a single dose of pregnant mares serumgonadotrophin and then are mated with normal males.1,l-bis(trifluoromethyl)-2,2-di(4 methoxyphenyl)- ethylene (the productof Example 4) suspended in sesame oil is orally administered in gradeddoses to numerically equal groups of these female rats for six daysstarting on TABLE II Compound of example: ED in mg./kg.-day

When the parent compound, 1,1-bis(trifiuoromethyl)-2,2-diphenylethylene, was used in a similar experiment, it had anactivity at ED of 0.11 mg./kg.-day.1,l-bis(trifluoromethyl)-2,2-diphenylethylene is a known compound, cf.W. J. Middleton and W. H. Sharkey, J. Org. Chem, 30, 1384 (1965).

The embodiments of the invention in which an exclusi-ve property orprivilege is claimed are defined as follows:

1. A compound of the formula 12 in which X is selected from H and OR;and R is selected from alkyl and hydroxyalkyl; each R having up totwelve carbon atoms.

2. 1,1-bis(trifluoromethyl) 2,2 di(4 ethoxyphenyl)- ethylene, thecompound of claim 1 in which X is OR and R is ethyl.

3. 1,1-bis(trifluoromethyl) 2,2 di(4 methoxyphenyl)-ethylene, thecompound of claim 1 in which X is OR and R is methyl.

4. 'l,1-bis(trifluorometh'yl) 2 (4 methoxyphenyD- Z-phenylethylene, thecompound of claim 1 in which X is H and R is methyl.

References Cited UNITED STATES PATENTS 3,237,200 2/1966 Barany et al.260 619 A 3,683,009 8/1972 Middleton 260--612 R OTHER REFERENCES Dixon,Jour. Org. Chem., vol. 21 (1956), pp. 400-403.

Miguel et al., Jour. Med. Chem., vol. 6 (1963), pp. 774- 780.

Middleton et al., Jour. Org. Chem., vol. 30 (1965), pp. 13841389.

BERNARD HELFIN, Primary Examiner US. Cl. X.R. 260-613 R 33 0 1mm STATESPATENT" mm" v CERTIFICATE OF CGRREG'HGN Patcnt No. jililJ- fi Baud W7&973

inventor) William John Middleton It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

F Col. 3, line 30., the formula should be:

Col. 4, line 5, should be 1,l-bis(trifluol'omethyl) 2-phenyl-2 2 C01. 2,line 9, correct the spelling of "cyclohexanoyl".

Signed and sealed this 8th day of October 1974,

Attest: A

MCCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner ofPatents

